Immune responses to infectious agents are complex usually involving activation of both the innate and adaptive immune systems. The adaptive system perceives pathogens as a collection of immunogenic determinants inducing both thymus-independent (TI) and thymus-dependent (TD) antibody responses. Protective vaccination has relied heavily on the principle of producing immunological memory to TD antigens through the induction of both long-lived antibody producing cells and recirculating non-antibody secreting precursor memory cells derived from the activation of follicular B cells. Recent studies have developed a new conceptual framework for understanding immune memory demonstrating that TI-2 antigens also induce long lived antibody protection by plasma cells and quiescent recirulating memory B cells. TI-2 responses are also unique in that they are comprised of Ig isotypes different than those associated with TD antigens and they are derived from B1 and marginal zone B cells, B cell subpopulations not normally activated by immunization with TD antigens. Responses to TI-2 antigens are more rapid than those to TD antigens and the B cell subpopulations responding express immunoglobulin repertoires distinct from that of follicular B cells. To date attempts to produce neutralizing antibodies to HIV have uniformly used TD antigens as immunogens. In the present studies we wish to test the hypothesis that a vaccine consisting of an HIV derived peptide conjugated to the high molecular weight polysaccharide Ficoll will act as a TI-2 antigen, capable of activating both murine and human B cells, and B cell subpopulations distinct from those induced by the TD form of the antigen. We further propose the antibodies produced by this immunization regimen will have broad neutralizing activity for HIV isolates. [unreadable] [unreadable] [unreadable]